Is BAP1 p.Pro474Leu (c.1421C>T) pathogenic?

BAP1 p.Pro474Leu (c.1421C>T) is classified Conflicting classifications of pathogenicity in BAP1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-29). AlphaMissense: likely benign (0.0866); Very rare (popmax 0.00668%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with BAP1 p.Pro474Leu (c.1421C>T)?

BAP1 p.Pro474Leu (c.1421C>T) is associated with hereditary neoplastic syndrome, BAP1-related tumor predisposition syndrome (ClinVar).

How common is BAP1 p.Pro474Leu (c.1421C>T) in the general population?

BAP1 p.Pro474Leu (c.1421C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about BAP1 p.Pro474Leu (c.1421C>T)?

AlphaMissense predicts likely benign (score 0.0866) — an in-silico prediction, not a clinical call.

BAP1 p.Pro474Leu

c.1421C>T · rs770422186 · VCV489618

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0866 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0866	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -7.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00668% East Asian · 3/44,896 alleles

Filtering AF 0.00239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.00279% 45/1,613,892 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,965
European (non-Finnish)	0.00322%	31,053
Admixed American	0.00167%	60,006
Remaining individualsnot grpmax-eligible	0.0016%	62,484
African / African-American	0.00134%	74,882
South Asian	0.0011%	91,094

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: BAP1
Protein: p.Pro474Leu
Coding: c.1421C>T
MANE Select: NM_007212 · reported on NM_004656
dbSNP: rs770422186
Type: single nucleotide variant
Location: chr3:52403724 (GRCh38)
Structure: AlphaFold pLDDT 78.27 · 28 PDB

Full BAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: BAP1-related tumor predisposition syndrome

Similar variants

BAP1 p.Pro474= Benign/Likely benign ★★ same residue
BAP1 p.Pro474Arg Uncertain significance ★ ⚠ same residue
BAP1 c.1117-1G>A Likely pathogenic ★★ same condition
BAP1 c.122+1G>A Pathogenic ★★ same condition
BAP1 c.122+1G>T Pathogenic/Likely pathogenic ★★ same condition
BAP1 c.122+5G>A Pathogenic/Likely pathogenic ★★ same condition
BAP1 c.122+5G>C Likely pathogenic ★★ same condition
BAP1 c.1251-1G>A Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/bap1-p-pro474leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown